Introduction to Nutrigenomics

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Introduction to Nutrigenomics

• Lecture 22
• April 13, 2009
• Dr. Quadro

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Improper diets are risk factors for diseases

• Epidemiological studies associate specific foods
  with incidence and severity of obesity, diabetes,
  cardiovascular, cancer and/or other chronic
  diseases.

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Nutrigenomics

• The study of the effects of diet on the activity
  of individuals genes and health

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• Dietary constituents can affect gene expression
  and/or genome structure

Effects on -Transcription -DNA structure
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Structure of Cells

• Plasma membrane
• Cytoplasm
• Nucleus (compartment where DNA is stored)

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Functions of Nucleus

• Keeps the DNA molecules of eukaryotic cells
  separate from metabolic machinery of cytoplasm
• Makes it easier to organize DNA and to copy it
  before parent cells divide into two daughter
  cells

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Deoxyribonucleic Acid (DNA)
Is the molecule of life It contains all the
information needed to build an organism The
genetic material
(http//siggy.chem.ucla.edu/tim/chemistry/DNA.jpg
)
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Role of the genetic material

• A genetic material must carry out two jobs
  duplicate itself and control the development of
  the rest of the cell in a specific way.
• -Francis Crick

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DNA is a chain of nucleotides

• Nucleotides are composed of
• -Sugar-deoxyribose
• -Phosphate group
• -Base-one of four types adenine (A), thymine
  (T)
• guanine (G),
  cytosine (C)

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Structure of DNA
Two nucleic acid chains running in opposite
directions The two nucleic acid chains are
coiled around a central axis to form a double
helix For each chain the backbone comes from
linking the pentose sugar bases between
nucleotides The bases face inward and pair in a
highly specific fashion with bases in the other
chain A only with T, G only with C Because of
this pairing, each strand is complementary to the
other 5 ACGTC 3 3 TGCAG 5 
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Gene molecular definition

• A gene is a segment of DNA which codes the
  formation of RNA which in turn directs the
  formation of a protein.

Genotype the genetic information
Phenotype the external features
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RNA is a chain of nucleotides
-Single chain of nucleotides

• -Nucleotides are composed of
• Sugar-ribose
• Phosphate group
• Base-one of four types adenine (A), uracile
  (U)
• guanine (G),
  cytosine (C)

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Gene expression the flow of genetic information
from DNA to protein via RNA
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The genetic information is coded by the sequence
of the nucleotides
RNA
Protein
The protein creates the phenotype
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The genetic information is coded by the sequence
of the nucleotides
RNA
Protein
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Nutrigenomics
Diet
Health or Disease
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Molecular nutrition
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Many genes are regulated by dietthrough the
interaction of a given food component with a
specific receptor or set of receptors
Diet plays a crucial role in chronic diseases
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..Again Transcription
Genes are flanked by untranscribed regions called
Promoters. This are DNA sequences near the
beginning of genes that signal RNA polymerase
where to begin transcription.
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Transcriptional regulation by vitamin A
RAR
RXR
Gene of interest
RARE
PROMOTER
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Transcription-factor pathways mediating
nutrient-gene interaction
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Functions of PPARs
PPARa
PPARg
PPARb

• Nutrient metabolism
• (lipid, glucose, AAs)
• - Proliferation
• - Inflammation

- Lipid and glucose metabolism - Cell cycle
control - Inflammation
- Lipid metabolism - Keratinocyte
differentiation - Inflammation
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PPARs are ligand activated transcription factors
Function
9 cis retinoic acid
fatty acids
PPAR
Proteinsynthesis
-

PPAR
RXR
DNA transcription
Gene
AGGTCAaAGGTCA
Response element
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Why are PUFAs healthy?
SREBP1SP1/NF-Y
PPAR

-
Fatty acid oxidation genes
Lipogenic genes
FA synthesisTriglyceride synthesis
b-Oxidation
VLDL-TG
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Estrogen Receptors
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Estrogen Receptors

• ER-a
• Uterus, testis, pituitary, ovary, epididymis, and
  adrenal gland.
• ER-b (Kuiper et al. 1996)
• brain, kidney, prostrate, ovary, lung, bladder,
  intestine, and epididymis.
• Membrane localized ER (Pietras and Szego, 1997)
• ER-a and b differ in C-terminal ligand binding
  domains and N-terminal transactivation domains.
  Highest homology in DNA binding domain.

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ER effects on different cell types
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Phytoestrogens
Aherne and OBrien, 2002. Nutrition 1875-81.
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Dietary Sources of Phytoestrogens
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Soy Phytoestrogens

• Genistein, daidzein, coumesterol, and equol bind
  to and transactivate both ER-??and ER-?
  (0.1-10mM)
• Genistetin has a higher affinity for ER?.
• Soy PEs effect cell cycle progression, growth,
  and differentiation. Have antioxidant and
  antiangiogenic activities.

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Phytoestrogens in Human Health

• Cancer prevention
• Post-menopausal supplement
• Prevention of osteoporosis
• Cardiovascular health
• Fertility
• Breast enhancement

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Nutrigenomics

• Nutrigenomics attempts to study the genome-wide
  influences of nutrition.
• From a nutrigenomics perspective, nutrients are
  dietary signals that are detected by the cellular
  sensor systems that influence gene and protein
  expression and, subsequently, metabolite
  production.
• Patterns of gene expression, protein expression
  and metabolite production in response to
  particular nutrients or nutritional regimes can
  be viewed as 'dietary signatures'.

Müller M,  Kersten S. Nutrigenomics Goals and
Perspectives. Nature Reviews Genetics 4, 315 -322
(2003)
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Nutrigenomics

• Nutrigenomics seeks to examine these dietary
  signatures in specific cells, tissues and
  organisms, and to understand how nutrition
  influences homeostasis.
• Nutrigenomics aims to identify the genes that
  influence the risk of diet-related diseases on a
  genome-wide scale, and to understand the
  mechanisms that underlie these genetic
  predispositions.

Müller M,  Kersten S. Nutrigenomics Goals and
Perspectives. Nature Reviews Genetics 4, 315 -322
(2003)
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Nutrigenomics
FoodsNutrition
Target GenesMechanismsPathways
SignaturesProfilesBiomarkers
Molecular Nutrition Genomics
NutritionalSystems Biology

• Identification of dietary signals
• Identification of dietary sensors
• Identification of target genes
• Reconstruction of signaling pathways

• Measurement of stress signatures
• Identification of early biomarkers

Large research consortiaBig money
Small research groupsSmall budgets
Complexity
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• Influence of diet on health depends upon an
  individuals genetic makeup

Personalized nutrition- diets based upon
genotype, nutritional requirements and
status It prevents and mitigate chronic
diseases
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Personalized diets?
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Diet and genes